Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol

ABSTRACT

A pharmaceutical formulation for prolonged release of the active ingredient 3-(3-dimethylamino-1-ethyl-2-methylpropyl)phenol or a pharmaceutically acceptable salt thereof in a matrix containing between 1 and 80 wt % of at least one pharmaceutically acceptable hydrophilic or hydrophobic polymer as a matrix forming agent and exhibiting in vivo the following release rate: 3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5 hours; 5 to 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour; 10 to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours; 15 to 82% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours; 30 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl -propyl)phenol released after 6 hours; more than 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12 hours; more than 70% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/242,800,filed Sep. 23, 2011, which in turn was a continuation of co-pendingapplication Ser. No. 10/831,368, filed Apr. 26, 2004, now abandoned,which in turn was a continuation of international patent application no.PCT/EP02/11809, filed Oct. 22, 2002, designating the United States ofAmerica, and published in German as WO 03/035053, the entire disclosureof which is incorporated herein by reference. Priority is claimed basedon Federal Republic of Germany patent application nos. DE 101 52 469.2,filed Oct. 24, 2001, and DE 102 48 309.4, filed Oct. 16, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to a slow-release pharmaceuticalformulation, containing3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceuticallyacceptable salt thereof in a matrix.

3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from Europeanpatent no. EP 693,475 as an analgesic pharmaceutical composition and canbe administered orally. Conventional formulations for oraladministration of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol leadto rapid release of the active ingredient in the gastrointestinal tract,so its analgesic action begins rapidly. At the same time, a rapidreduction in the action is observed. Therefore, the treatment ofpronounced chronic pain with3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol formerly requiredadministration of the pharmaceutical composition at relatively shortintervals, for example four to eight times daily, to ensure anadequately high concentration of active ingredient in the patient'sblood plasma. However, the need for frequent dosing easily leads toerrors in administration and to undesirable variations in concentrationin the plasma which are detrimental to patient compliance and thetherapeutic benefit, particularly when treating chronically painfulconditions. It is therefore desirable to have a slow releasepharmaceutical composition (retard formulation) for oral administrationof the active ingredient,3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.

In the prior art, retard formulations are generally known for a largenumber of different active ingredients. Conventional forms ofretardation include coating retardation and matrix retardation.

In coating retardation as described, for example, in published Germanpatent application no. DE 36 25 458, the nucleus of a pharmaceuticalcomposition containing an active ingredient is provided with a coatingwhich consists of one or more hydrophilic and/or hydrophobic polymersand slows down release of the active ingredient.

In matrix retardation, the active ingredient is contained in a matrixwhich is formed from one or more excipients and controls release of theactive ingredient. Published German patent application no. DE 33 09 516,for example, accordingly discloses a process for producing matrixformulations with hydroxypropylmethyl cellulose (HPMC) as excipient andslow release, in part, of the active ingredient, the excipient making upnot more than one third of the weight of the formulation and consistingof at least one hydroxypropylmethyl cellulose having a methoxy contentof 16 to 24% by weight, a hydroxypropyl content of 4 to 32% by weightand a numerically averaged molecular weight of at least 50,000. Theformulations disclosed in DE 33 09 516 A1 contain HPMCs havingviscosities (in a 2% by weight aqueous solution at 20° C.) between 15and 30,000 cPs (15 to 30,000 mPa·s). Release behavior which isindependent of the pH of the dissolution medium is not disclosed in DE33 09 516 A1.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide apharmaceutical formulation which achieves slow release of3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol.

This object and other objects are achieved in accordance with thepresent invention by a slow-release pharmaceutical formulationcontaining 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof in a matrix with slow releaseof active ingredient, in which the matrix contains 1 to 80% by weight,preferably 5 to 80% by weight, of one or more hydrophilic or hydrophobicpolymers as pharmaceutically acceptable matrix forming agents and hasthe following release rate in vitro, measured by the Ph. Eur. PaddleMethod at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37° C. anddetected using a UV spectrometer:

-   -   3 to 35% by weight (based on 100% by weight active ingredient)        of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released        after 0.5 hours;    -   5 to 50% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        1 hour;    -   10 to 75% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        2 hours;    -   15 to 82% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        3 hours;    -   30 to 97% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        6 hours;    -   more than 50% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        12 hours;    -   more than 70% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        18 hours, and    -   more than 80% by weight of        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after        24 hours.        It has surprisingly been found that the formulation according to        the invention releases the active ingredient,        3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, slowly when        administered orally and is therefore suitable for administration        at intervals of at least 12 hours. The formulation according to        the invention therefore enables pain therapy, during which the        analgesic, 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol,        only has to be administered once daily, for example at 24 hour        intervals, or twice daily, preferably at 12 hourly intervals, in        order to ensure an adequate concentration of the active        ingredient in the plasma. A corresponding duration of efficacy        and the maintenance of an adequate level in the blood plasma are        demonstrated by simulation studies and experimental        investigations.

It is particularly surprising that the formulation according to theinvention not only ensures long-lasting therapeutic efficacy over arelatively long period (at least 12 hours) due to the slow release ofthe active ingredient, but at the same time allows the active ingredientto start flowing rapidly in the plasma when the pharmaceuticalcomposition is first administered, leading to a rapid onset of painrelief in the patient. Therefore, the pain suffered by a patient canrapidly be alleviated when the formulation according to the invention isadministered without the analgesic action quickly fading again. Theformulation according to the invention therefore combines properties ofa formulation with immediate release of active ingredient—rapid painrelief due to adequately high concentration of active ingredient justafter administration of the pharmaceutical composition—with propertiesof a formulation having slow release—long-lasting analgesic action dueto maintenance of an adequately high level of active ingredient over aprolonged time. By taking the analgesic in the formulation according tothe invention, the patient can effectively combat his pain acutely and,at the same time, treat it effectively over a prolonged period withoutfurther measures and merely by regular administration at 12 (or 24)hourly intervals.

The active ingredient of the formulation according to the invention iscontained in a slow release matrix. It is also conceivable, however,that the active ingredient be contained in a matrix with conventionalrelease behavior and the slow release be achieved by a retardingcoating.

In a further possibility the slow release behavior is achieved by anosmotically driven release system.

If the formulation according to the invention contains a slow releasematrix, the matrix contains 1 to 80% by weight of one or morehydrophilic or hydrophobic polymers as pharmaceutically acceptablematrix forming agents, for example rubbers, cellulose ethers, celluloseesters, acrylic resins, materials derived from proteins, fats, waxes,fatty alcohols or fatty acid esters. When using hydrophilic polymers asmatrix forming agents, it is preferable for the matrix to comprise 5 to80% by weight matrix forming agents.

The present invention also relates to a pharmaceutical formulation whichcontains 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof in a matrix with slow releaseof active ingredient, in which the matrix contains 1 to 80% by weight,in particular 5 to 80 by weight, of one or more hydrophilic orhydrophobic polymers as pharmaceutically acceptable matrix formingagents and which comprise cellulose ethers and/or cellulose estershaving a viscosity (determined using a Pharm. Eu. capillaryviscosimeter) of 3,000 to 150,000 mPa·s in a 2% by weight aqueoussolution at 20° C. as pharmaceutically acceptable matrix forming agents.These compositions have the above-mentioned release profile according tothe invention.

Preferred pharmaceutically acceptable matrix forming agents includecellulose ethers and/or cellulose esters having a viscosity between10,000, in particular 50,000 mPa·s, and 150,000 mPa·s in a 2% by weightaqueous solution at 20° C.

Particularly suitable pharmaceutically acceptable matrix forming agentsmay be selected from the group consisting of hydroxypropylmethylcelluloses (HPMC), hydroxyethyl celluloses, hydroxypropyl celluloses(HPC), methyl celluloses, ethyl celluloses and carboxymethyl cellulosesand are selected, in particular, from the group consisting of HPMCs,hydroxyethyl celluloses and HPCs. HPMCs having a viscosity of approx.100,000 mPa·s measured in a 2% by weight aqueous solution at 20° C. aremost preferred.

The active ingredient,3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, exists as such, i.e.as a free base, but also in the form of pharmaceutically acceptablesalts, for example as a hydrochloride. Preparation of the free base isknown from published European patent application no. EP 693,475. WhereEP 693,475 does not also disclose the preparation of pharmaceuticallyacceptable salts such as hydrochloride, these may be obtained from thefree base by processes generally known in the art.

3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol has two asymmetriccenters, so the compound can exist in the form of four differentstereoisomers. In the formulation according to the invention3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol can exist as a mixtureof all four diastereomers in any ratio, but also as a mixture of two orthree of the four stereoisomers or in pure stereoisomer form. Preferredstereoisomers include (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, which, inthe formulation according to the invention, can exist as a mixture, inparticular as a 1:1 mixture (racemate) or particularly preferably inpure isomer form. For the purposes of the present invention, therefore,the term “active ingredient” denotes3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as a mixture ofvarious stereoisomers thereof or as one pure stereoisomer thereof as afree base or in the form of a pharmaceutically acceptable saltrespectively.

In the pharmaceutical compositions according to the invention, the slowrelease active ingredient content is preferably between 0.5 and 85% byweight and the content of pharmaceutically acceptable matrix formingagents between 8 and 40% by weight. Particularly preferredpharmaceutical compositions have a slow release active ingredientcontent between 3 and 70% by weight, in particular between 8 and 66% byweight, and a content of pharmaceutically acceptable matrix formingagents between 10 and 35% by weight, in particular between 10 and 30% byweight. If enantiomerically pure(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol (or amixture of the (+) and (−) enantiomers with a large excess of the (+)enantiomer) is used as active ingredient, it is particularly preferredif the active ingredient content lies at the lower limit, i.e. between0.5 and 25% by weight (based on the total weight). If enantiomericallypure (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol (or amixture of the (+) and (−) enantiomers with a large excess of the (−)enantiomer) is used as active ingredient, it is particularly preferredif the active ingredient content lies between 16 and 66% by weight.

Further components of the matrix of the formulation according to theinvention may optionally include digestible long-chain (i.e. with 8 to50 carbon atoms, preferably 12 to 50 carbon atoms) unsubstituted orsubstituted hydrocarbons such as fatty alcohols, fatty acid glycerylesters, mineral and vegetable oils as well as waxes. Hydrocarbons havinga melting point between 25° and 90° C. are preferred. Fatty alcohols areparticularly preferred and lauryl alcohol, myristyl alcohol, stearylalcohol, cetyl alcohol and cetylstearyl alcohol are more particularlypreferred. Their content in the matrix may be 0 to 60% by weight. Thematrix can alternatively or additionally contain polyethylene glycols ina content of 0 to 60% by weight.

The pharmaceutical formulations according to the invention can alsocontain, as further components, pharmaceutically acceptable auxiliariessuch as fillers, for example lactose, microcrystalline cellulose (MCC)or calcium hydrogen phosphate as well as glidants, lubricants and flowregulators such as talcum, magnesium stearate, stearic acid and/orhighly dispersed silicon dioxide, of which the total content in thetablet may be between 0 and 80% by weight, preferably between 5 and 65%by weight.

The release rate of an active ingredient from an administrable formfrequently depends on the pH of the release medium. This can vary in apH range from less than 1 to about 8 as the pharmaceutical compositionpasses through the gastrointestinal tract. These variations also canvary from one person to another. One and the same person can also have adifferent pH/time profile during passage through the gastrointestinaltract from one administration to another. Thus, if the release rate ofthe active ingredient from the pharmaceutical composition is dependenton the pH, this can lead to different release rates in vivo andtherefore different biocompatibility.

Surprisingly, however, the release profiles of the active ingredient(either in the form of the base or of a pharmaceutically acceptable saltthereof) from a pharmaceutical formulation according to the inventionare independent of the pH which can occur physiologically during passagethrough the gastrointestinal tract. The release profiles with an ambientpH of 1.2, 4.0 and 6.8 are identical to one another and also incomparison to the release during a pH/time profile from pH 1.2 via pH2.3 and pH 6.8 to pH 7.2.

It has been found that it is immaterial for achieving the slow releaseof active ingredient from the formulation according to the invention,which preferably exists in tablet form, whether a water-soluble filler,for example lactose, an insoluble filler which does not swell in anaqueous medium, for example calcium hydrogen phosphate, or an insolublefiller which swells in an aqueous medium, for example microcrystallinecellulose, is used as filler with otherwise unchanged values andunchanged composition of the tablet, based on the active ingredient, thematrix forming agent and the optional components. All thesepharmaceutical compositions exhibit a corresponding release behavior.

It is also surprising that, in the compositions according to theinvention with a given amount of active ingredient, the quantity ofmatrix forming agent and the quantity of optional components can eachvary over a relatively large range without affecting the therapeuticefficacy of at least 12 hours or with twice daily administration(providing that the above-mentioned limits on the quantity of activeingredient, matrix forming agent and further optional components areadhered to). Efficacy over at least 12 hours is assured, for example,with an active ingredient content of approx. 32.25% by weight (based onthe weight of the total composition) in a composition of approx. 12.9%by weight HPMC having a viscosity of 100,000 mPa·s as matrix formingagent and a content of approx. 52.6% by weight of, for example, MCC asfiller and also in a composition of approx. 25.8% by weight of the sameHPMC and approx. 39.7% by weight MCC (or lactose monohydrate) withotherwise identical amounts of glidant, lubricant and flow regulators.The same applies to compositions according to the invention with ahigher or lower active ingredient content within the specified limits.

It has also extremely surprisingly been found that, when thepharmaceutical formulations according to the invention with slow releaseof the active ingredient are administered to human volunteers, abiocompatibility which is the same as in formulations with immediaterelease of active ingredients is unexpectedly achieved despite the highfirst-pass effect for the active ingredient.

Compositions according to the invention which have a t_(max) value inthe in vivo plasma concentration/time graph of between 2 and 10 hours,in particular between 3.5 and 6 hours and more particularly preferablybetween 4 and 5.5 hours after oral administration of the composition,i.e. compositions which yield peak plasma levels during said periods,are also preferred.

As active ingredient, the formulation according to the inventioncontains 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as suchand/or as a pharmaceutically acceptable salt in an amount typically of2.5 to 800 mg, in particular 5 to 400 mg, more particularly preferably10 to 250 mg (weight of the active ingredient3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as hydrochloride) perdose unit. The release behavior of the formulation according to theinvention is not affected by the exact amount of the active ingredientprovided that the above-mentioned limits are adhered to. Due to thedifferent active strength of the two particularly preferred enantiomers(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, it ispreferred if the stronger(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol exists inan amount of 2.5 to 80 mg, in particular 5 to 40 mg and moreparticularly preferably in an amount of 10 to 25 mg active ingredient(based on the hydrochloride) in the formulations according to theinvention, while the(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol preferablyis present in an amount of 25 to 800 mg, in particular 50 to 400 mg andmore particularly preferably in an amount of 100 to 250 mg activeingredient (based on the hydrochloride) in the formulations according tothe invention, more specifically on condition that the above-mentionedlimits are adhered to.

Within the scope of this invention, the term “pharmaceuticallyacceptable salt” of the active ingredient refers to a salt of the activeingredient which is physiologically acceptable for pharmaceutical use,in particular when administered to mammals and/or humans.Pharmaceutically acceptable salts of this type may be formed, forexample, with inorganic or organic acids.

The pharmaceutical formulations according to the invention can existboth as a simple tablet and as a coated tablet, for example as a filmtablet or dragee. The tablets are typically round and biconvex, butoblong tablet shapes which allow the tablet to be divided are alsopossible. Granules, spheroids, pellets or microcapsules which are pouredinto sachets or capsules or may be compressed to disintegrating tabletsare also possible within the scope of the invention.

One or more coating layers may be used for the coated tablets. Suitablecoating materials include known hydroxypropylmethyl celluloses having alow viscosity of approx. 1 to 100 mPa·s and a low molecular weight of<10,000 (for example Pharmacoat 606 with a viscosity of 6 mPa·s in a 2%by weight aqueous solution at 20° C.), which only slightly influence therelease profile of the pharmaceutical compositions according to theinvention. Diffusion coatings known to persons skilled in the art andbased, for example, on swellable but water-insoluble poly(meth)acrylateslead to modulation of the slow release of the active ingredients frompharmaceutical formulations according to the invention. The tablet corewhich contains the active ingredient, releases the active ingredientslowly and has an active ingredient content preferably between 0.5 and85% by weight, particularly preferably between 3 and 70% by weight andmore particularly preferably between 8 and 66% by weight. The tabletcore can be sheathed with additional active ingredient which is releasedas an initial dose without retardation by various processes known topersons skilled in the art, for example dragee production, spraying fromsolutions or suspensions or by application of powder, but without thisbeing absolutely essential for the desired slow release with asimultaneous rapid initial flow of the active ingredient for rapid painrelief on first administration of the pharmaceutical formulationaccording to the invention. Multilayered and shell-type tabletsrepresent further embodiments, in which3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceuticallyacceptable salt thereof is released slowly in one or more layers of themultilayer tablet with an active ingredient content preferably between0.5 and 85% by weight, particularly preferably between 3 and 70% byweight, and more particularly preferably between 8 and 66% by weight, orin the core of the shell-type tablet with an active ingredient contentpreferably between 0.5 and 85% by weight, particularly preferablybetween 3 and 70% by weight, and more particularly preferably between 8and 66% by weight by a pharmaceutically acceptable matrix forming agent,and the release of the active ingredient takes place without retardationin one or more layers of the multilayer tablet or the outer shell layerof the shell-type tablets. Multilayer and shell-type tablets can containone or more coatings which are free from active ingredients.

Instead of a slow release matrix in the slow release pharmaceuticalformulation, it is also possible to use a normal release matrix with acoating which retards release of the active ingredient. For example, theactive ingredient can be contained in a conventional matrix ofmicrocrystalline cellulose and optionally further pharmaceuticalauxiliaries such as binders, fillers, glidants, lubricants and flowregulators, which are covered or coated with a material controlling theslow release of the active ingredient in an aqueous medium. Suitablecoating agents include, for example, water-insoluble waxes and polymerssuch as polymethacrylates (Eudragit or the like) or water-insolublecelluloses, in particular ethyl cellulose. The coating material canoptionally also contain water-soluble polymers such as polyvinylpyrrolidone, water-soluble celluloses such as hydroxypropylmethylcellulose or hydroxypropyl cellulose, other water-soluble agents such asPolysorbate 80 or hydrophilic pore-forming agents such as polyethyleneglycol, lactose or mannitol.

As an alternative or a supplement to the possibilities of a slow releasematrix in the prolonged release pharmaceutical formulation or of anormal release matrix with a coating which retards the release of theactive ingredient, an osmotically driven release system can also be usedto achieve a slow release. With a release system of this type,preferably an oral system, at least one, preferably all, surface(s) ofthe release system, preferably those which are in contact or which maycome into contact with the release medium, are semi-permeable,preferably provided with a semi-permeable coating, so the surfaces arepermeable to the release medium but substantially, and preferablycompletely, impermeable to the active ingredient, whereby the surfaceand/or optionally the coating comprises at least one opening forreleasing the active ingredient. The active ingredient3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceuticallyacceptable salt thereof, preferably(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof and/or(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof or a mixture thereof can, butdoes not have to, be present in a matrix. This is preferably taken tomean a system in tablet form with a delivery opening, an osmoticpharmaceutical composition core, a semi-permeable membrane and apolymeric part which exerts pressure. A useful example of such a systemis the OROS® system from ALZA Corporation, USA, details of which areavailable on the Alza Corporation internet site and/or in productliterature of Alza Corporation. These include in particular the OROS®Push-Pull™ system, the OROS® Delayed Push-Pull™ system, the OROS®Multi-Layer Push-Pull™ system, the OROS® Push-Stick System and incertain cases the L-OROS™. Embodiments and examples of the actualproduction of osmotically driven release systems can be found in U.S.Pat. Nos. 4,765,989; 4,783,337 and 4,612,008, the complete disclosuresof which are incorporated herein by reference.

The compositions according to the invention may be produced, forexample, by the following general processes: weighed amounts of thecomponents of the composition (active ingredient, matrix forming agentand optional components) successively introduced and then screened on aconventional screening machine, for example a Quadro Comil U10 screeningmachine using, for example, a conventional screen size of approx. 0.813mm. The screened material is then mixed in a container mixer, forexample a Bohle container mixer. Typical mixer operating conditions are:duration approx. 15 min +45 seconds at a speed of 20±1 rpm. Theresulting powder mixture is subsequently compressed to a tablet on atablet press, for example a Korsch EKO tablet press with a round diecurved in the form of a dragee having a diameter of 10 mm.Alternatively, the powder mixture can be compacted and the compactssubsequently screened (Comill 3 mm friction macerating sieve andsubsequent 1.2 mm round hole screen), the resulting granules then beingcompressed in the above-described manner with addition of lubricant (forexample magnesium stearate) for example on an EKO tablet press with 10mm round dies. Granulation can also be carried out by wet granulationusing aqueous or organic solvents. Aqueous solvents with or without asuitable binder are preferred. The production process can readily beadapted to the respective requirements and the desired form ofadministration by procedures well known to persons skilled in the art.

The production of pharmaceutical formulations according to the inventionis characterized by high repeatability of the release properties of theresulting compositions containing3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceuticallyacceptable salt thereof. The release profile of pharmaceuticalcompositions according to the invention has proven to be stable for astorage time of at least one year under conventional storage conditionsaccording to ICH Q1AR Stability Testing Guidelines.

With once or twice daily administration of a pharmaceutical formulationaccording to the invention by the patient, good therapeutic efficacy isreliably achieved in the case of continuously strong pain.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph of average serum concentrations achieved by differingpharmaceutical formulations in a clinical trial.

EXAMPLES

The following examples serve to illustrate the present invention andpreferred embodiments, but do not restrict its scope.

Example 1

A batch of 1,000 matrix tablets was produced as described below havingwith the following composition per tablet:

(—)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000  80mg from Shinetsu, 100,000 mPa · s Microcrystalline cellulose (Avicel PH102 from FMC) 123 mg Highly dispersed silicon dioxide  4 mg Magnesiumstearate  3 mg Total amount 310 mgAll components were weighed in and screened on a Quadro Comil U10screening machine using a screen size of 0.813 mm, mixed in a containermixer (Bohle LM 40) for 15 minutes ±15 seconds at a speed of 20±1 rpmand pressed on a Korsch EKO eccentric press to tablets curved in themanner of dragees with a diameter of 10 mm, a radius of curvature of 8mm and an average tablet weight of 310 mg. The in vitro release wasdetermined by the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH 6.8buffer according to Ph. Eur. at 37° C. and with detection using a UVspectrometer, and is reproduced in the following table:

Time (min) Total amount of active ingredient released [%] 0 0 30 18 6027 120 41 180 50 240 59 360 71 480 80 600 87 720 93

Example 2

Using a process similar to that described in Example 1, 3,000 matrixtablets were produced having the following composition per tablet:

(—)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 200 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000  80mg from Shinetsu, 100,000 mPa · s Microcrystalline cellulose (Avicel PH102 from FMC)  23 mg Highly dispersed silicon dioxide  4 mg Magnesiumstearate  3 mg Total amount 310 mg

The in vitro release was determined as in Example 1.

Time (min) Total amount of active ingredient released [%] 0 0 30 19 6030 120 46 180 58 240 68 360 84 480 93 720 99

Example 3

Using a process similar to that described in Example 1, a batch of 3,000matrix tablets were produced having the following composition pertablet:

(—)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000  40mg from Shinetsu, 100,000 mPa · s Microcrystalline cellulose (Avicel PH102 from FMC) 163 mg Highly dispersed silicon dioxide  4 mg Magnesiumstearate  3 mg Total amount 310 mgThe in vitro release was determined as in Example 1. In addition, therelease was determined under otherwise identical conditions at stirringspeeds of 50 and 100 rpm.

Total amount of Total amount of Total amount of active ingredient activeingredient active ingredient Time released [%] released [%] released [%](min) at 50 rpm at 75 rpm at 100 rpm 0 0 0 0 30 20 20 21 60 35 33 35 12054 51 53 180 67 63 66 240 76 73 76 360 89 87 89 480 97 95 97 600 100 100100

Example 4

Using a process similar to that described in Example 1, a batch of 200matrix tablets was produced having the following composition per tablet:

(—)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa · s Lactose monohydrate 230 (Meggle) 123 mgHighly dispersed silicon dioxide  4 mg Magnesium stearate  3 mg Totalamount 310 mgThe in vitro release was determined as in Example 1.

Time (min) Total amount of active ingredient released [%] 0 0 30 16 6026 120 39 180 49 240 57 360 71 480 81 600 87 720 92

Example 5

Matrix tablets with the following composition per tablet

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 40 mg100,000 from Shinetsu, 100,000 mPa · s Cellactose 80 (Meggle) 163 mgHighly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Totalamount 310 mgwere produced by a process similar to that described in Example 1 in abatch size of 100 tablets.

The in vitro release was determined as an Example 1.

Time Total amount of active (min) ingredient released [%] 0 0 30 18 6031 120 48 180 61 240 71 360 84 480 91 600 95 720 97

Example 6

Matrix tablets with the following composition per tablet

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 80 mg100,000 from Shinetsu, 100,000 mPa · s Ludipress (BASF) 123 mg Highlydispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310mgwere produced by a process similar to that described in Example 1 in abatch size of 100 tablets.

The in vitro release was determined as in Example 1.

Time Total amount of active (min) ingredient released [%] 0 0 30 17 6027 120 40 180 51 240 59 360 72 480 82 600 89 720 93

Example 7

Matrix tablets with the following composition per tablet

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 50 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 40 mg100,000 from Shinetsu, 100,000 mPa · s Microcrystalline cellulose(Avicel PH 102 from FMC) 163 mg Lactose 200 (Meggle) 50 mg Highlydispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310mgwere produced by a process similar to that described in Example 1 in abatch size of 200 tablets.

The in vitro release was determined as in Example 1.

Time Total amount of active (min) ingredient released [%] 0 0 30 18 6031 120 49 180 61 240 70 360 82 480 90 600 94 720 96

Example 8

Matrix tablets with the following composition per tablet

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Cellactose (Meggle) 72.5 mg Hydroxyethyl cellulose(Natrosol 250 HX from Herkules) 12.5 mg Cutina HR (Henkel) 130 mg Talcum3 mg Magnesium stearate 2 mg Total amount 320 mgwere produced as follows in a batch size of 200 tablets. The activeingredient, Cellactose, Natrosol and Cutina were mixed then heated to80° C. in a drying oven and granulated in a Kenwood Chef kitchen mixer.The cooled granules were screened through a 1 mm screen. After blendingwith magnesium stearate and talcum, the granules were pressed on a EKOeccentric press (Korsch) to 6×15 mm size oblong tablets with a breakingnotch.

The in vitro release was determined as in Example 1.

Time Total amount of active (min) ingredient released [%] 0 0 30 28 6039 120 56 180 68 240 80 360 97 390 99

Example 9

Matrix tablets with the following composition per tablet

(+)-(1S,2S)3-(3-dimethylamino-1-ethyl-2-methyl- 10 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 80 mg100,000 from Shinetsu, 100,000 mPa · s Microcrystalline cellulose(Avicel PH 102 from FMC) 213 mg Lactose 200 (Meggle) 50 mg Highlydispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310mgwere produced by a process similar to that described in Example 1 in abatch size of 100 tablets.

The in vitro release was determined as in Example 1.

Time Total amount of active (min) ingredient released [%] 0 0 30 15 6024 120 36 180 44 240 51 360 61 480 69 600 75 720 79

Example 10

Matrix tablets with the following composition per tablet:

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 80 mg100,000 from Shinetsu, 100,000 mPa · s Microcrystalline cellulose(Avicel PH 102 from FMC) 63 mg Highly dispersed silicon dioxide 4 mgMagnesium stearate 3 mg Total amount 250 mgwere produced by a process similar to that described in Example 1 in abatch size of 100 tablets.

The in vitro release was determined under the following conditions:

-   (A) application of the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH    7.2 buffer to USP 22 at 37° C. and with detection using a UV    spectrometer;-   (B) application of the Ph. Eur. Paddle Method at 75 rpm, a pH of 1.2    being adjusted from 0 to 30 min, a pH of 2.3 from 30 to 120 min, a    pH of 6.5 from 120 to 180 min and a pH of 7.2 for the remaining test    period. The table shows the results for both experimental    conditions:

Total amount of active Total amount of active Time ingredient released[%} ingredient released [%} (min) under condition (A) under condition(B) 0 0 0 30 19 20 60 29 30 120 43 44 180 54 55 240 63 65 360 78 80 48087 90 600 94 97 720 98 100The experiment shows that the release behavior of the formulationsaccording to the invention is independent of the pH of the releasemedium.

Example 11

Pellets were produced as described below having the followingcomposition:

(−)-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl- 100 mg propyl)phenolhydrochloride Low-substituted hydroxypropyl cellulose (L-HPC 75 mg LH 31from Shinetsu) Aquacoat (aqueous ethyl cellulose dispersion from FMC) 20mg (calculated as dry substance) Microcrystalline cellulose (Avicel PH101 from FMC) 75 mg Dibutyl sebacate (DBS) 4 mg Tween 80 0.4 mg Totalamount 274.4 mgThe active ingredient, Avicel and L-HPC were mixed for 10 minutes in aplanetary mixer (Kenwood K Mixer) and then granulated with water. Themoist granules were extruded in a Nica extruder with a 0.8×0.8 mm matrixand then rounded for 10 min in the Nica spheronizer at 500 rpm (1 kgloading). The pellets were dried overnight in a drying oven at 50° C.and then classified into screen fractions.

Pellets measuring 0.6 to 1.0 mm (yields about 95%) were coated in theWSG (smooth GPCG1 with a Wurster insert) at incoming air temperatures of60° C. (product temperature 40° C.) with an aqueous dispersion ofAquacoat and DBS (20%, calculated on Aquacoat solids content), so theyhad an increase in weight of 9.8% (based on the original weight). Thedispersion was produced in accordance with the manufacturer'sinstructions (FMC), the DBS together with the Tween 80 being homogenizedin a proportion of the water and then being added to the dilute Aquacoatdispersion. The final dispersion had a solids content of 20% by weightand was stirred for at least 3 hours. The coated pellets were dried inthe WSG and tempered in the drying oven (2 hours at 60° C.). The releasewas tested as in Example 1, but by the basket method at 100 rpm.

Time Total amount of active (min) ingredient released [%] 0 0 30 5 60 15120 28 180 43 240 56 360 73 480 82 600 87 720 90

Clinical Trial

In a monocentric, open, randomized individual dose four-way crossovertrial, various forms of administration of(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolhydrochloride (active ingredient) were administered to sixteen healthymale white subjects aged from 18 to 45 years, to determinephaimacokinetic data. Data was determined experimentally by HPLCanalysis. The following were administered:

“Capsule 100 mg”: capsules with immediate release of the activeingredient and 100 mg of active ingredient

“Capsule 25 mg”: capsules with immediate release of the activeingredient and 25 mg of active ingredient

“Tablet 100 mg”: tablet according to Example 1 (100 mg of activeingredient)

“Tablet 200 mg”: tablet according to Example 2 (200 mg of activeingredient) The capsules were white-opaque hard gelatine capsules ofsize 0 EL with a filling of 360 mg, which were made up as follows:

“Capsule 100 mg”: 100 mg(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolhydrochloride, 152 mg microcrystalline cellulose, 8 mg Aerosil, 20 mgmagnesium stearate and 80 mg Primojel (sodium carboxymethyl starch typeA from Avebe);

“Capsule 25 mg”: 25 mg(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolhydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil, 20 mgmagnesium stearate and 80 mg Primojel (sodium carboxymethyl starch typeA from Avebe))

The essential pharmacokinetic data are shown in the following table andthe characteristic of the experimentally determined average serumconcentration in FIG. 1.

“Capsule “Capsule “Tablet “Tablet Parameter 25 mg” 100 mg” 100 mg” 200mg” AUC [ng · h/ml] 69 ± 14 318 ± 66  300 ± 51 667 ± 141 C_(max) [ng/ml]14 ± 4  64 ± 19 23 ± 5 51 ± 13 t_(max) [h] 1.2 ± 0.4 1.5 ± 0.9  4.6 ±1.3 4.8 ± 1.1 MRT* [h] 5.8 ± 0.7 5.9 ± 0.9 10.7 ± 1.5 10.3 ± 1.1  HVD**3.5 ± 1.2 3.6 ± 1.1 12.4 ± 2.8 11.9 ± 2.3  *MRT = “Mean Residence Time”**HVD = “Half Value Duration”

On the one hand, a comparison of “Capsule 100 mg” and “Tablet 100 mg”immediately shows that the formulations according to the inventionexcellently fulfil the task of providing a pharmaceutical formulationcontaining a 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol with slowrelease of active ingredient. On the other hand, when “Tablet 100 mg” iscompared with “Tablet 200 mg” there is also very advantageous doseproportionality in the release behavior.

However, this also shows that the two compositions according to theinvention, “Tablet 100 mg” and “Tablet 200 mg” release the activeingredient in a discernible amount but more slowly at the beginning thanthe two formulations with immediate release; with the two retardedformulations, however, the plasma level is higher than 10 ng/ml afteronly one hour and still sufficiently high after 16 hours to ensure ananalgesic action. Simulation studies for “Tablet 100 mg” also showedthat, with repeated administration of the pharmaceutical composition at12 hourly intervals, serum levels are achieved which do not fall below20 ng/ml, so good analgesic efficacy is ensured by twice dailyadministration. This represents great progress for the treatment, inparticular of chronic painful conditions, and allows a significantimprovement in patient compliance.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention my occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

What is claimed is:
 1. A slow-release pharmaceutical formulationcontaining 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof as active ingredient in amatrix, wherein the matrix contains 1 to 80% by weight of one or morepharmaceutically acceptable hydrophilic or hydrophobic polymers asmatrix forming agents and has the following release rate in vitro,measured by the Ph. Eur. Paddle Method at 75 rpm in a buffer (to Ph.Eur.) at a pH of 6.8 at 37° C. and detected using a UV spectrometer: 3to 35% by weight (based on 100% by weight active ingredient)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 0.5hours, 5 to 50% by weight3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour,10 to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolreleased after 2 hours, 15 to 82% by weight3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3hours, 30 to 97% by weight3-(3-dimethylamino-1l-ethyl-2-methyl-propyl)phenol released after 6hours, more than 50% by weight3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 12hours, more than 70% by weight3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 18hours, and more than 80% by weight3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24hours.
 2. A pharmaceutical composition according to claim 1, wherein thematrix forming agents comprise cellulose ethers, cellulose esters or amixture thereof having a viscosity of 10,000 to 150,000 mPa·s in a 2% byweight solution at 20° C.
 3. A pharmaceutical composition according toclaim 1, wherein the matrix forming agents comprise cellulose ethers,cellulose esters or a mixture thereof having a viscosity of 50,000 to150,000 mPa·s in a 2% by weight solution at 20° C.
 4. A pharmaceuticalcomposition according to claim 1, wherein the matrix forming agentcomprises at least one substance selected from the group consisting ofhydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses,hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses andcarboxymethyl celluloses.
 5. A pharmaceutical composition according toclaim 1, wherein the matrix forming agent comprises at least onesubstance selected from the group consisting of hydroxypropylmethylcelluloses, hydroxyethyl celluloses, hydroxypropyl celluloses andhydroxypropyl celluloses.
 6. A pharmaceutical composition according toclaim 1, wherein said composition contains from 0.5 to 85% by weightactive ingredient and from 8 to 40% by weight matrix forming agents. 7.A pharmaceutical composition according to claim 1, wherein saidcomposition comprises from 3 to 70% by weight active ingredient and from10 to 35% by weight matrix forming agents.
 8. A pharmaceuticalcomposition according to claim 7, wherein said composition comprisesfrom 8 to 66% by weight active ingredient and from 10 to 30% by weightmatrix forming agents.
 9. A pharmaceutical composition according toclaim 1, wherein a peak plasma level of the active ingredient isobtained in vivo 2 to 10 hours after administration of the composition.10. A pharmaceutical composition according to claim 9, wherein the peakplasma level of the active ingredient is obtained in vivo 3.5 to 6 hoursafter administration of the composition.
 11. A pharmaceuticalformulation according to claim 1, wherein the active ingredientcomprises (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolor a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalformulation according to claim 1, wherein the active ingredientcomprises (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolor a pharmaceutically acceptable salt thereof.
 13. A tablet for twicedaily oral administration of3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, said tabletcontaining a pharmaceutical formulation according to claim
 1. 14. Aslow-release pharmaceutical formulation containing3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceuticallyacceptable salt thereof as active ingredient in a matrix, wherein thematrix contains 1 to 80% by weight of one or more pharmaceuticallyacceptable hydrophilic or hydrophobic polymers as matrix forming agentsand comprises cellulose ethers cellulose esters or a mixture thereofhaving a viscosity of 3,000 to 150,000 mPa·s in a 2% by weight aqueoussolution at 20° C.
 15. A pharmaceutical composition according to claim14, wherein the matrix forming agents comprise cellulose ethers,cellulose esters or a mixture thereof having a viscosity of 10,000 to150,000 mPa·s in a 2% by weight solution at 20° C.
 16. A pharmaceuticalcomposition according to claim 14, wherein the matrix forming agentscomprise cellulose ethers, cellulose esters or a mixture thereof havinga viscosity of 50,000 to 150,000 mPa·s in a 2% by weight solution at 20°C.
 17. A pharmaceutical composition according to claim 14, wherein thematrix forming agent comprises at least one substance selected from thegroup consisting of hydroxypropylmethyl celluloses (HPMC), hydroxyethylcelluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethylcelluloses and carboxymethyl celluloses.
 18. A pharmaceuticalcomposition according to claim 14, wherein the matrix forming agentcomprises at least one substance selected from the group consisting ofhydroxypropylmethyl celluloses, hydroxyethyl celluloses, hydroxypropylcelluloses and hydroxypropyl celluloses.
 19. A pharmaceuticalcomposition according to claim 14, wherein said composition containsfrom 0.5 to 85% by weight active ingredient and from 8 to 40% by weightmatrix forming agents.
 20. A pharmaceutical composition according toclaim 14, wherein said composition comprises from 3 to 70% by weightactive ingredient and from 10 to 35% by weight matrix forming agents.21. A pharmaceutical composition according to claim 20, wherein saidcomposition comprises from 8 to 66% by weight active ingredient and from10 to 30% by weight matrix forming agents.
 22. A pharmaceuticalcomposition according to claim 14, wherein a peak plasma level of theactive ingredient is obtained in vivo 2 to 10 hours after administrationof the composition.
 23. A pharmaceutical composition according to claim22, wherein the peak plasma level of the active ingredient is obtainedin vivo 3.5 to 6 hours after administration of the composition.
 24. Apharmaceutical formulation according to claim 14, wherein the activeingredient comprises(+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or apharmaceutically acceptable salt thereof.
 25. A pharmaceuticalformulation according to claim 14, wherein the active ingredientcomprises (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenolor a pharmaceutically acceptable salt thereof.
 26. A tablet for twicedaily oral administration of3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, said tabletcontaining a pharmaceutical formulation according to claim 14.